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Ulrich Renner, Uberto Pagotto, Eduardo Arzt and Günter Karl Stalla

Renner U, Pagotto U, Arzt E, Stalla GK. Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review. Eur J Endocrinol 1996;135:515–32. ISSN 0804–4643

In addition to the classical hormones, the production of numerous polypeptide growth factors, cytokines, vasogenic substances and neuropeptides by pituitary cells has been demonstrated. Expression of the corresponding receptors on pituitary cells enables these factors to influence growth and function of the pituitary by auto- or paracrine mechanisms. Thus, in addition to the external endocrine control of pituitary growth and function, an intrinsic intercellular communication network seems to be involved in the control of pituitary homeostasis. The cell-to-cell communication may be of importance for the pre- and postnatal differentiation of the pituitary, for the regulation of the cellular composition of the gland (by balancing mitosis and apoptosis and controlling angiogenesis) and for the adaption of pituitary function to altered physiological conditions (i.e. stress, pregnancy and diseases). Differences in the expression of or the response to the above-mentioned factors in pituitary adenomas indicate that these substances are of importance for pituitary tumorigenesis. Disturbances of auto-/paracrine mechanisms may not necessarily be involved in the tumor initiation processes, but they may play a crucial role in tumor progression. After the initial transformation, the clonal expansion of the tumor cell is dependent on its ability to escape either from the inhibitory action of growth suppressing factors or to develop an autocrine mechanism that allows autonomous growth. In summary, therefore, this review outlines the potential role of polypeptide growth factors, cytokines and vasogenic peptides as auto-/paracrine-acting substances in normal pituitary and pituitary adenomas.

Ulrich Renner, Max-Planck-Institute of Psychiatry, Clinical Institute, Department of Endocrinology, Kraepelinstr. 10, D-80804 Munich, Germany

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Valentina Vicennati, Silvia Genghini, Rosaria De Iasio, Francesca Pasqui, Uberto Pagotto and Renato Pasquali

Objective: We measured blood levels of obestatin, total ghrelin, and the ghrelin/obestatin ratio and their relationship with anthropometric and metabolic parameters, adiponectin and insulin resistance, in overweight/obese and normal-weight women.

Design: Outpatients Unit of Endocrinology of the S Orsola-Malpighi Hospital of Bologna, Italy.

Methods: Fasting obestatin, ghrelin, adiponectin and lipid levels, fasting and glucose-stimulated oral glucose tolerance test insulin, and glucose levels were measured in 20 overweight/obese and 12 controls. The fasting ghrelin/obestatin ratio was calculated; the homeostasis model assessment-IR (HOMA-IR) and insulin sensitivity index (ISIcomposite) were calculated as indices of insulin resistance.

Results: Obese women had higher obestatin and lower ghrelin blood levels, and a lower ghrelin/obestatin ratio compared with controls. In all subjects, obestatin was significantly and positively correlated with total cholesterol and triglycerides, but not with ghrelin, anthropometric, and metabolic parameters. In the obese women, however, obestatin and ghrelin concentrations were positively correlated. By contrast, the ghrelin/obestatin ratio was significantly and negatively correlated with body mass index, waist, waist-to-hip ratio, fasting insulin, and HOMA-IR, and positively with ISIcomposite but not with adiponectin. None of these parameters were correlated with the ghrelin/obestatin ratio in the obese.

Conclusions: Increased obestatin, decreased ghrelin levels, and a decreased ghrelin/obestatin ratio characterize obesity in women. This supports the hypothesis that the imbalance of ghrelin and obestatin may have a role in the pathophysiology of obesity. On the other hand, some relevant differences between our data on circulating levels of obestatin and the ghrelin/obestatin ratio in obese subjects and those reported in the few studies published so far imply that further research is needed.

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Renato Pasquali, Alessandra Gambineri, Carla Cavazza, Daniela Ibarra Gasparini, Walter Ciampaglia, Graciela Estela Cognigni and Uberto Pagotto

Background

Treatment of obesity improves all features of the polycystic ovary syndrome (PCOS). There is, however, a heterogeneous response to weight loss, and predictive factors are unknown.

Objective

This follow-up study aimed to investigate obese women with PCOS treated with a long-term lifestyle program to evaluate responsiveness and predictability.

Methods

One hundred PCOS women meeting the criteria for selection were invited to participate and 65 of them agreed. Lifestyle intervention had consisted of a 1200–1400 kcal/day diet for 6 months, followed by mild calorie restriction and physical activity. The protocol, which was similar at baseline and follow-up, included anthropometry, clinical evaluation, pelvic ultrasound, and laboratory investigations. The mean follow-up period was 20.4±12.5 months.

Results

After the follow-up period, women were reclassified into three groups according to the persistence (group 1, 15.4%), partial (group 2, 47.7%), or complete (group 3, 36.9%) disappearance of the categorical features of PCOS (hyperandrogenism, menses, and ovulatory dysfunctions). Duration of the follow-up and extent of weight loss were similar among the three groups, as were fasting and glucose-stimulated insulin and indices of insulin resistance. Baseline waist circumference, waist to hip ratio (WHR), and androstenedione blood levels were negatively correlated with a better outcome in the univariate analysis. However, only basal androstenedione values persisted to a highly significant extent (P<0.001) in the multivariate analysis.

Conclusions

Responsiveness to weight loss in overweight/obese PCOS women varies considerably and more than one third of women may achieve full recovery. These findings add new perspectives to the impact of obesity on the pathophysiology of PCOS.

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Guido Di Dalmazi, Valentina Vicennati, Eleonora Rinaldi, Antonio Maria Morselli-Labate, Emanuela Giampalma, Cristina Mosconi, Uberto Pagotto and Renato Pasquali

Background

Subclinical Cushing's syndrome (SCS) is defined as alterations in hypothalamic–pituitary–adrenal axis without classic signs/symptoms of glucocorticoid excess. Whether SCS leads to metabolic and cardiovascular diseases is still controversial.

Aim

To evaluate the prevalence of hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), ischemic stroke, osteoporosis, and fractures, and their relationship to increasing patterns of subclinical hypercortisolism, in patients with nonsecreting adrenal adenomas (NSA) and SCS.

Methods

Using the 1 mg dexamethasone suppression test (DST), 348 patients were classified as follows: 203 were defined as NSA and 19 SCS, using the most stringent cutoff values (<50 and >138 nmol/l respectively). Patients with cortisol post-DST (50–138 nmol/l) were considered as intermediate phenotypes and classified as minor (n=71) and major (n=55) using plasma ACTH and/or urinary free cortisol as additional diagnostic tools.

Results

SCS patients showed higher prevalence of T2D, CHD, osteoporosis, and fractures with respect to NSA. Intermediate phenotypes also showed higher prevalence of CHD and T2D with respect to NSA. The prevalence of all clinical outcomes was not different between intermediate phenotype patients, which were therefore considered as a single group (IP) for multivariate logistic regression analysis: both IP and SCS-secreting patterns showed a significant association with CHD (odds ratio (OR), 4.09; 95% confidence interval (CI), 1.47–11.38 and OR, 6.10; 95% CI, 1.41–26.49 respectively), independently of other potential risk factors. SCS was also independently associated with osteoporosis (OR, 5.94; 95% CI, 1.79–19.68).

Conclusions

Patterns of increasing subclinical hypercortisolism in adrenal adenomas are associated with increased prevalence of adverse metabolic and cardiovascular outcomes, independently of other potential risk factors.

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Alessandra Gambineri, Flaminia Fanelli, Federica Tomassoni, Alessandra Munarini, Uberto Pagotto, Ruth Andrew, Brian R Walker and Renato Pasquali

Context

Abnormal cortisol metabolism in polycystic ovary syndrome (PCOS) has been invoked as a cause of secondary activation of the hypothalamic–pituitary–adrenal axis and hence androgen excess. However, this is based on urinary excretion of cortisol metabolites, which cannot detect tissue-specific changes in metabolism and may be confounded by obesity.

Objective

To assess cortisol clearance and whole-body and tissue-specific activities of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1 (HSD11B1)) in PCOS.

Design

Case–control study.

Setting

Medical center.

Patients

A total of 20 overweight–obese unmedicated Caucasian women with PCOS, aged 18–45 years, and 20 Caucasian controls matched for age, BMI, body fat distribution, and HSD11B1 genotypes (rs846910 and rs12086634).

Main outcome measures

Cortisol metabolites were measured in 24 h urine. During steady-state 9,11,12,12-[2H]4-cortisol infusion, cortisol clearance was calculated and whole-body HSD11B1 activity was assessed as the rate of appearance of 9,12,12-2H3-cortisol (d3-cortisol). Hepatic HSD11B1 activity was quantified as the generation of plasma cortisol following an oral dose of cortisone. Subcutaneous adipose HSD11B1 activity and HSD11B1 mRNA were measured, ex vivo, in biopsies.

Results

Urinary cortisol metabolite excretion, deuterated cortisol clearance, and the rate of appearance of d3-cortisol did not differ between patients with PCOS and controls. However, hepatic HSD11B1 conversion of oral cortisone to cortisol was impaired (P<0.05), whereas subcutaneous abdominal adipose tissue HSD11B1 mRNA levels and activity were increased (P<0.05) in women with PCOS when compared with controls.

Conclusions

Tissue-specific dysregulation of HSD11B1 is a feature of PCOS, over and above obesity, whereas increased clearance of cortisol may result from obesity rather than PCOS.

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Alessandra Gambineri, Federica Tomassoni, Alessandra Munarini, Roland H Stimson, Roberto Mioni, Uberto Pagotto, Karen E Chapman, Ruth Andrew, Vilma Mantovani, Renato Pasquali and Brian R Walker

Objective

Regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within liver and adipose tissue may be of pathophysiological importance in obesity and the metabolic syndrome. single nucleotide polymorphisms (SNPs) in HSD11B1, the gene encoding 11β-HSD1, have been associated with type 2 diabetes and hypertension in population-based cohort studies, and with hyperandrogenism in patients with the polycystic ovary syndrome (PCOS). However, the functional consequences of these SNPs for in vivo 11β-HSD1 expression and activity are unknown.

Methods

We explored associations of well-characterised hormonal and metabolic phenotypes with two common SNPs (rs846910 and rs12086634) in HSD11B1 in 600 women (300 with PCOS) and investigated 11β-HSD1 expression and activity in a nested study of 40 women from this cohort.

Results

HSD11B1 genotypes (as single SNPs and as the combination of the two minor allele SNPs) were not associated with PCOS. Women who were heterozygous for rs846910 A and homozygous for rs12086634 T (GA, TT genotype) had a higher risk of metabolic syndrome, regardless of the diagnosis of PCOS (odds ratio in the whole cohort=2.77 (95% confidence interval (CI) 1.16–6.67), P=0.023). In the nested cohort, women with the GA, TT genotype had higher HSD11B1 mRNA levels in adipose tissue, and higher rates of appearance of cortisol and d3-cortisol (16.1±0.7 nmol/min versus 12.1±1.1, P=0.044) during 9,11,12,12-2H4-cortisol (d4-cortisol) steady-state infusion.

Conclusions

We conclude that, in a population of Southern European Caucasian women with and without PCOS, alleles of HSD11B1 containing the two SNPs rs846910 A and rs12086634 T confer increased 11β-HSD1 expression and activity, which associates with the metabolic syndrome.

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Roberta Giordano, Andrea Picu, Uberto Pagotto, Rosaria De Iasio, Lorenza Bonelli, Flavia Prodam, Fabio Broglio, Lisa Marafetti, Renato Pasquali, Mauro Maccario, Ezio Ghigo and Emanuela Arvat

Objective: Ghrelin exerts a wide spectrum of endocrine and non-endocrine actions. The stomach is the major source of circulating ghrelin levels that are negatively associated with body mass, insulin and glucose levels. The role of glucocorticoids in ghrelin secretion and action is still unclear.

Design: In 8 patients with Cushing’s disease (CD, BMI 29.8 ± 1.6 kg/m2), 7 normal (NS) and 6 obese subjects (OB, BMI 32.9 ± 1.1 kg/m2) we studied: a) total ghrelin levels (every 15 min over 3 h) and their correlation with BMI, insulin, glucose, homeostatic model assessment (HOMA) index, ACTH and cortisol levels; b) GH, ACTH, cortisol, insulin and glucose responses to acylated ghrelin administration (1.0 μg/kg i.v. at 0 min).

Results: CD patients had BMI, insulin and glucose levels as well as HOMA index higher than those in NS (P < 0.05) but similar to those in OB. Despite this, total ghrelin levels in CD were similar to those in NS and both were higher (P < 0.05) than those in OB. No correlation was found among total ghrelin and BMI, insulin, glucose, ACTH and cortisol levels in CD patients. The GH responses to ghrelin in CD and OB were similar and both were lower (P < 0.002) than those in NS. In CD ghrelin induced exaggerated ACTH and cortisol responses clearly higher (P < 0.005) than in OB and NS. Ghrelin administration increased glucose in all groups; insulin levels showed slight decrease that was significant (P < 0.05) in OB only.

Conclusions: Hypercortisolism in humans is associated with impaired ghrelin secretion and action. In fact, total ghrelin secretion in CD is not reduced despite increased BMI, insulin and glucose levels, while the GH and ACTH responses to acylated ghrelin are clearly reduced and enhanced, respectively.

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Alessandra Gambineri, Valentina Vicennati, Guido Di Dalmazi, Carla Pelusi, Paola Altieri, Flaminia Fanelli, Andrea Repaci, Silvia Garelli, Danilo Ribichini and Uberto Pagotto